The design, synthesis, characterization, DNA binding properties, and cytotoxic activity of a novel series of hybrids, namely, a mol. combination of the natural antibiotic distamycin A and the antineoplastic agent uramustine, are reported, and the structure-activity relationships are discussed. This homologous series 29-34 consisted of the minor groove binder distamycin A joined to uramustine (uracil mustard) by suitable aliph. carboxylic acid moieties contg. a flexible polymethylene chain that is variable in length (CH2)n, where n = 1-6. All the hybrid compds. in this series exhibit enhanced activity compared to both distamycin A and uramustine derivs. 22-27 used for conjugation, giving IC50 values in the range 7.26-0.07 μM following a 1 h exposure of human leukemic K562 cells, with maximal activity shown when n = 6. The distance between the uramustine and distamycin frame is crucial for the cytotoxicity, with compds. having linker lengths of four to six being at least 20-fold more cytotoxic than liker lengths one to three. Taq polymerase stop expts. demonstrated selective covalent binding of uramustine-distamycin hybrids to A/T rich DNA sequences, which was again more efficient with compds. 32-34 with a longer linker length. Two consequences can be derived from our study: (a) the distamycin moiety directs binding to the minor groove of A/T rich DNA sequences and, consequently, is responsible for the alkylation regioselectivity found in footprinting studies; (b) the higher flexibility due to a longer linker between the distamycin and uracil moieties allows the formation of complexes with the mustard moiety situated more deeply in the minor groove and, hence, with better alkylating properties.
Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A
BARALDI, Pier Giovanni;ROMAGNOLI, Romeo;
2002
Abstract
The design, synthesis, characterization, DNA binding properties, and cytotoxic activity of a novel series of hybrids, namely, a mol. combination of the natural antibiotic distamycin A and the antineoplastic agent uramustine, are reported, and the structure-activity relationships are discussed. This homologous series 29-34 consisted of the minor groove binder distamycin A joined to uramustine (uracil mustard) by suitable aliph. carboxylic acid moieties contg. a flexible polymethylene chain that is variable in length (CH2)n, where n = 1-6. All the hybrid compds. in this series exhibit enhanced activity compared to both distamycin A and uramustine derivs. 22-27 used for conjugation, giving IC50 values in the range 7.26-0.07 μM following a 1 h exposure of human leukemic K562 cells, with maximal activity shown when n = 6. The distance between the uramustine and distamycin frame is crucial for the cytotoxicity, with compds. having linker lengths of four to six being at least 20-fold more cytotoxic than liker lengths one to three. Taq polymerase stop expts. demonstrated selective covalent binding of uramustine-distamycin hybrids to A/T rich DNA sequences, which was again more efficient with compds. 32-34 with a longer linker length. Two consequences can be derived from our study: (a) the distamycin moiety directs binding to the minor groove of A/T rich DNA sequences and, consequently, is responsible for the alkylation regioselectivity found in footprinting studies; (b) the higher flexibility due to a longer linker between the distamycin and uracil moieties allows the formation of complexes with the mustard moiety situated more deeply in the minor groove and, hence, with better alkylating properties.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
